Environment and Gene Effects on Brain and Behavior

环境和基因对大脑和行为的影响

• 批准号: 8291304
• 负责人: JAY S SCHNEIDER
• 金额: $ 35.06万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291304
• 关键词: Acute; Adult; Affect; Animals; Area; Astrocytes; Attention; Attenuated; Behavior; Behavioral; Bioinformatics; Brain; Brain Chemistry; Brain Injuries; Candidate Disease Gene; Child; Chronic; Cognitive deficits; Data; Databases; Development; Dose; Early treatment; Emotional; Environment; Exposure to; Female; Frequencies; Gender; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Variation; Genotype; Geography; Hippocampus (Brain); Hispanics; Housing; Human; Intervention; Knowledge; Laboratories; Lead; Lead Poisoning; Learning; Memory; Metabolic Pathway; Microarray Analysis; Modification; Molecular; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neurosciences; Neurotoxins; Outcome; Porphobilinogen Synthase; Predisposition; Race; Rat Strains; Rattus; Regulatory Pathway; Reporting; Research; Role; Signal Pathway; Socioeconomic Status; Structure; Surveys; Toxic effect; Toxicokinetics; Toxicology; Toxin; base; blood lead; brain behavior; cDNA Arrays; environmental enrichment for laboratory animals; gene environment interaction; lead exposure; male; motor deficit; nervous system development; neurochemistry; neurotoxicity; neurotrophic factor; novel; response; sex; social

The developing brain is a particularly vulnerable target for lead with developmental lead exposure resulting in cognitive and motor deficits that persist into adulthood. Although the effects of lead on the developing brain have been studied for decades, there are gaps in our understanding of how genetic background and environment may modify lead's influences on nervous system development and function. Different environmental milieus may have powerful effects on the response of the brain to lead. For example, environmental enrichment could have potential neuroprotective effects against developmental exposure to lead whereas an impoverished environment may exacerbate the neurotoxicity. In addition to environment, genetic background may also modify the outcome from developmental lead exposure, although at this point, this has not been examined systematically. Thus, our proposed research has the following specific aims: Specific Aim 1. Examine the influence of genetic background on lead induced behavioral and molecular deficits in the hippocampus. Using gene expression arrays and bioinformatics, we will first survey the normal developmental gene expression profile for the hippocampus, a structure known to be sensitive to developmental lead toxicity in 4 strains of rats typically used for neuroscience or toxicology studies. We then will examine changes in these expression profiles following developmental lead exposure. We hypothesize that rats of different genetic backgrounds will have different behavioral and gene expression responses to similar lead exposures. Data derived from this study will lead to the first gene expression database for lead toxicity and advance our understanding of the metabolic, signaling and regulatory pathways that may be disturbed by developmental lead exposure. Information on the influence of genetic background on the response to this toxin may help in development of new strategies for intervention. Specific Aim 2. Assess the extent to which different environments modify behavioral and molecular deficits associated with developmental lead exposure. These studies will examine the effects of different housing environments on lead-induced deficits in spatial learning and memory and initial candidate gene expression (i.e., neurotrophic factor and NMDA receptor subtype expression) in the hippocampus. We hypothesize that animals raised in a social but impoverished environment will have more severe deficits and that animals reared in enriched environments and that the latter will be at least partially protected against the detrimental effects of lead exposure regardless of dose or type of exposure. Our research will not only examine the role of genetics in influencing the outcome from lead exposure but may demonstrate that the effects of lead on the brain are not immutable. Early intervention with therapy based on the principles of environmental enrichment might prove useful for attenuating at least some lead-related functional deficits. The proposed research will provide new data on the role of genetics in influencing the outcome from developmental lead exposure by assessing how different types and levels of developmental lead exposure interacts with genetic variation to result in brain damage. Additionally, examination of how rearing in different environments modify behavioral and molecular deficits associated with development lead exposure may demonstrate that the effects of lead on the brain are not immutable and that early intervention with therapy based on the principles of environmental enrichment might prove useful for attenuating at least some lead-related functional deficits.

发育中的大脑是铅特别容易受到伤害的目标，发育中的铅暴露会导致 认知和运动缺陷持续到成年。尽管铅对发育中的大脑有影响 虽然已经研究了几十年，但我们对遗传背景和基因如何发挥作用的理解存在差距。 环境可能会改变铅对神经系统发育和功能的影响。不同的 环境环境可能对大脑对铅的反应产生强大的影响。例如， 环境丰富可能对铅的发育暴露具有潜在的神经保护作用 而贫困的环境可能会加剧神经毒性。除了环境因素，还有遗传因素 背景也可能会改变发育铅暴露的结果，尽管在这一点上，这已经 没有经过系统的考察。因此，我们提出的研究有以下具体目标： 具体目标 1. 检查遗传背景对铅诱发的行为和分子缺陷的影响 海马体。利用基因表达阵列和生物信息学，我们将首先调查正常发育 海马体的基因表达谱，一种已知对发育铅毒性敏感的结构 在通常用于神经科学或毒理学研究的 4 种大鼠中。然后我们将检查这些方面的变化 发育性铅暴露后的表达谱。我们假设不同基因的老鼠 背景对相似的铅暴露会有不同的行为和基因表达反应。数据 这项研究的成果将产生第一个铅毒性基因表达数据库，并推进我们的研究 了解可能受发育干扰的代谢、信号传导和调节途径 铅接触。有关遗传背景对该毒素反应的影响的信息可能有助于 制定新的干预策略。具体目标 2. 评估不同的程度 环境改变了与发育性铅暴露相关的行为和分子缺陷。这些 研究将探讨不同的住房环境对铅引起的空间学习缺陷的影响 记忆和初始候选基因表达（即神经营养因子和 NMDA 受体亚型 表达）在海马体中。我们假设动物在社会但贫困的环境中长大 环境将出现更严重的赤字，在丰富的环境中饲养的动物以及 后者将至少部分受到保护，免受铅暴露的有害影响，无论剂量或 暴露类型。我们的研究不仅将检验遗传学在影响铅结果中的作用 但可能表明铅对大脑的影响并非一成不变。早期干预 基于环境富集原理的治疗可能被证明有助于至少减弱一些 与铅相关的功能缺陷。拟议的研究将提供关于遗传学在影响人类健康方面的作用的新数据。 通过评估不同类型和水平的铅暴露的发育结果 发育期铅暴露与遗传变异相互作用，导致大脑 损害。此外，检查不同环境中的饲养方式如何改变 与发育铅暴露相关的行为和分子缺陷可能 证明铅对大脑的影响不是一成不变的，而且早期 基于环境丰富原则的治疗干预可能 证明对于减轻至少一些与铅相关的功能缺陷是有用的。